Moxifloxacin is a broad-spectrum fluoroquinolone antibacterial agent, used for treating respiratory infections (pneumonia, chronic sinusitis, chronic bronchitis) sold in the hydrochloride form from Bayer AG under the name of Avelox® and Avalox®. It is also sold by Alcon Inc. in a low-dosage form for ophthalmic use under the name of Vigamox®.
Moxifloxacin of Formula I and having the chemical name of 1-cyclopropyl-7-[(1S,6S)-2,8-diazabicyclo [4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid, is characterized by a fluoroquinolone structure, similar to that of other two antibiotics of the same class (Gatifloxacin and Balofloxacin), and a side chain consisting of (4aS,7aS)-octahydro-1H -pyrrole[3,4-b]pyridine.

The fluoroquinolone intermediate of Formula (II), with the 8-methoxy group and the one with the 8-fluorine group of Formula (VIII) are both commercially available products.
The (4aS, 7aS)-octahydro-1H-pyrrole[3,4-b]pyridine, also called the (S,S)-2,8-diazabicyiclo[4.3.0]nonane and having CAS RN [151213-40-0] of Formula (III), is the Moxifloxacin side chain and is the synthesis key intermediate as it has two chiral centers, both with S configuration, is optically active and levogyrous. The preparation of the same is also described in the two Italian patent applications MI2009A001353 and MI2009A000332 both issued to FIS Fabbrica Italiana Sintetici Spa which provide an optimized optical resolution process and a regio and stereo-selective synthesis process of bio-enzymatic type respectively.
A first prior art synthesis process of Moxifloxacin hydrochloride described in EP 550903 comprises the coupling reaction between 1-cyclopropril -6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acid of Formula II
with the intermediate (4aS, 7aS)-octahydro-1H -pyrrole[3,4-b]pyridine of Formula III in the presence of base:

Due to the low regioselectivity of the reaction, however, the product obtained contains the isomer 6 impurity of Formula (V)
as the major impurity, which is difficult to separate from the product as this is a position isomer.
The required chromatographic purification on silica gel column results in the obtainment of the same in low yields.
WO 2008/138759 describes a process for preparing Moxifloxacin hydrochloride monohydrate where the coupling reaction between 1-cyclopropril-6,7-difluoro -1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acid with (S,S)-2,8-diazabicyclo[4.3.0]nonane is carried out in the absence of a base and the Moxifloxacin is isolated as the L-Tartrate or Fumarate or p-Ditoluiltartrate to be purified from the isomer 6 impurity, then it is converted to Moxifloxacin hydrochloride.
A second prior art method for the synthesis of Moxifloxacin described in WO 2005/012285 comprises the reaction between 1-cyclopropyl-6,7-difluoro-1,4-dihydro -8-methoxy-4-oxo-3-quinolinic acid ethyl ester of Formula (VII)

with boric acid and acetic anhydride to form an intermediate borate complex with 95% yield, which is reacted with (4aS, 7aS)-octahydro-1H-pyrrole[3,4-b]pyridine of Formula (III) with 72% yield, the ester and complex being subsequently hydrolyzed, and then salified to give Moxifloxacin hydrochloride with 91% yield, with 62% total molar yield.
In WO 2008/059223, a similar process is used as above, wherein, however, the complex is generated using boric acide and proprionic anhydride in place of acetic anhydride.
A third method reported in WO 2006/134491 provides reacting 1-cyclopropril-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acid of Formula (II) with boron trifluoride etherate to give a difluoroborate intermediate which is reacted with (S,S) -2,8-diazabicyclo[4.3.0]nonane of Formula (III) in the presence of a base with 92% yield thereby obtaining a Moxifloxacin difluoroborate complex which is hydrolyzed and salified to give Moxifloxacin hydrochloride with 42 to 55% total yield.
Finally, the Moxifloxacin synthesis has been carried out, as discussed in EP 1832587, by means of a similar method as above, the latter being carried out one-pot and including silanization prior to complexation by means of boron trifluoride.
The methods described above result in unsatisfying yields and suffer from using toxic reactants such as boron trifluoride.